Infliximab therapy in a child with Kawasaki disease 2 weeks after receiving rotavirus vaccination

Kawasaki disease (KD) is an acute vasculitis of unknown etiology, and the development of coronary artery aneurysms (CAAs) is the most common cardiovascular complication. The standard treatment for KD is intravenous immunoglobulin (IVIG); however, corticosteroids, infliximab (IFX), cyclosporine, and plasma exchange are recommended for IVIG-resistant KD. IFX, a tumor necrosis factor-alpha (TNF-α) inhibitor, has been shown to reduce inflammation and prevent CAA progression. Although IFX administration soon after live vaccination is not strictly contraindicated in Japan or other countries, several guidelines, including those from the Centers for Disease Control, the UK Green Book,1, 2 and the Japanese Society of Pediatric Infectious Diseases, recommend waiting at least 4 weeks after live vaccine administration before initiating immunosuppressive therapy. However, in clinical practice, IFX is sometimes considered when urgent treatment is required. We herein report a 5-month-old boy with IVIG-resistant KD who was treated with IFX 2 weeks after rotavirus vaccine administration. The patient presented with a fever, rash, conjunctival injection, erythematous lips, and swelling of the extremities. Blood tests showed the following: white blood cell count, 14,100/μL (76.1% neutrophils); platelet count, 380,000/μL; C-reactive protein (CRP) level, 17.9 mg/dL, and aspartate aminotransferase level, 28 IU/L. The patient was diagnosed with KD and admitted to the hospital. IVIG therapy was administered on Days 4 and 6; however, the patient developed therapeutic resistance. Although IFX was considered third-line therapy, he had received oral rotavirus vaccination (RotaTeq®, Merck & Co., Inc., Rahway, NJ, USA) 2 weeks prior. Therefore, plasma exchange therapy was performed on Days 7–9 after transfer to our hospital; however, the fever persisted. Given the clinical circumstances, we provided comprehensive counseling to his family regarding the potential risks and benefits of infliximab therapy. After obtaining informed consent, with negative results for tuberculosis and viral hepatitis, infliximab (5 mg/kg) was administered on Day 10, and symptoms rapidly improved, with the CRP level decreasing from 15.2 mg/dL before administration to 3.3 mg/dL afterward. Initial echocardiography at the time of transfer revealed a right CAA measuring 2.3 mm (z-score 3.11), which subsequently progressed to bilateral CAAs by Day 10 (right: 3.3 mm, z-score 5.8; left: 2.7 mm, z-score 3.7). Owing to persistently elevated CRP levels (3.0 mg/dL), cyclosporine was initiated on Day 20 and continued for 10 days after explanation to the parents. By Day 31, echocardiography demonstrated further progression to large CAAs: right coronary artery 6.5 mm (z-score 11.1); left main coronary artery 6.1 mm (z-score 10.8); and left anterior descending artery 4.3 mm (z-score 6.3) (Figure 1a). The patient was discharged on oral aspirin and warfarin and followed up as an outpatient. Although both infliximab and cyclosporine were administered, no symptoms indicative of vaccine-related complications were observed. At 10 months old, selective coronary angiography revealed complete regression of the bilateral CAAs, allowing for discontinuation of warfarin (Figure 1b,c). This case supports the safety and potential efficacy of IFX administration 2 weeks after rotavirus vaccination in IVIG-resistant KD. Although current guidelines generally recommend avoiding IFX in patients who have received BCG or other live vaccines within 3–6 months, recent studies suggest that single-dose IFX following live vaccines, such as rotavirus, may not significantly increase the risk of infection.3-5 Rotavirus vaccine replication is largely restricted to the intestinal mucosa, where protection is induced mainly through IgA responses, and rotavirus-specific CD4+ T cells that produce TNF-α or IFN-γ are rarely induced.6 Thus, mucosal antibody responses rather than systemic T cell cytokines appear to be central to protection, and TNF-α inhibition by IFX is unlikely to significantly compromise vaccine-related immunity in immunocompetent infants. Consistent with this finding, our patient did not develop prolonged gastrointestinal symptoms or other adverse events after IFX therapy. These findings suggest that the current recommendations for delaying immunosuppressant therapy after live vaccination may be overly conservative.7 In the present case, the patient rapidly became afebrile after IFX administration, and clinical symptoms such as rash, cervical lymphadenopathy, and irritability resolved; however, a slight elevation in CRP persisted, necessitating the addition of cyclosporine. Delayed initiation of infliximab or cyclosporine therapy may have contributed to the development or progression of Kawasaki disease–associated coronary artery aneurysms, suggesting that current treatment strategies for Kawasaki disease following vaccination may need to be reconsidered. In conclusion, carefully monitored IFX therapy may be both acceptable and clinically beneficial in patients who develop IVIG-resistant KD shortly after receiving a live vaccination, particularly in those with existing CAAs. D. S. involved the treatment of this patient in Kyushu Hospital, Japan Community Healthcare Organization, drafted the initial manuscript, and carried out the initial analysis. J. M. involved the treatment of this patient in Kyushu Hospital, Japan Community Healthcare Organization, designed the data collection instruments, coordinated and supervised data collection, carried out the initial analysis, and reviewed and revised the manuscript. D. T., Y. S., and M. W. involved the treatment of this patient in Kyushu Hospital, Japan Community Healthcare Organization, carried out the initial analysis and reviewed and revised the manuscript. Y. N. and T. O. involved the treatment of this patient in Kokura Medical Center, National Hospital Organization, carried out the initial analysis and reviewed and revised the manuscript. All authors gave approval of the final version. Verbal consent was obtained from the patient's families for the publication of clinical notes and was recorded in the medical chart. We thank Drs Atsushi Tanaka, Yuki Minematsu, Nobuya Minematsu, Masaki Ikeda, and Hirotaka Koga (Department of Pediatrics, Kyushu Hospital, Japan Community Healthcare Organization) for their involvement in the treatment of this patient and for providing precise medical advice. We appreciate the help of Dr. Brian Quinn (Japan Medical Communication, Fukuoka, Japan) for editing the manuscript. The authors declare no conflict of interest. The data that support the findings of this study are available on request from the corresponding author. The data are not publicly available due to privacy or ethical restrictions.